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According to the National Institutes of Health’s definition, translational research aims to treat human disease via utilization of existing knowledge from both basic and patient-oriented research. Translational research forms the bridge between “bench (preclinical and basic research) and bedside (clinical research),” where exciting discoveries at the bench are delivered to patients in need and, through reverse feedback, clinical questions and needs arising from patient care go back to the bench to inspire mechanistic research and new solutions.

While it sounds simple, there are multiple barriers in the field of translational research in the clinical environment. In particular, the speed of early novel drug development is hindered by lack of development strategies based on true understanding of the drugs’ mechanism, lack of high-quality hypothesis-based clinical trial designs that can test the applicability of novel drugs, and lack of solid preclinical testing to define the best synergistic existing therapies to combine with new drugs to induce true efficacy in patients.

There is an urgent demand from academic translational/clinical researchers and Pharma for a robust preclinical system to test novel drugs’ best application strategies via a dedicated preclinical team prior to, or in parallel with, the actual testing of the drug in patients.

A new program in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center seeks to address these challenges.

It is becoming clear that simply validating the drug toxicity, pharmacokinetic and pharmacodynamic marker monitoring, and biomarker development is not sufficient to launch a successful novel drug in this modern era. Instead, preclinical testing can support the rationale of each drug to reduce the current risk of development based on tight collaboration among academic, clinical, and translational investigators.

For example, screening to discover the best synergistic partner for a drug (via RNA interference or the new CRISPR/cas9 gene-knockout system), drug testing in clinically relevant animal models (patient-derived xenograft and immunocompetent tumor models based on mice or a genetic engineering model), and integration of bioinformatics analysis of patient sample-based omics data will all contribute to the likelihood of the clinical success of a drug.

In the end, the goal is to reduce the risk of the project by expanding disease indications of the drug of interest, identifying clinically relevant predictive biomarkers, understanding resistance mechanisms, and designing novel combination therapies. These approaches will successfully bring a clear path for the drug development complement of the results of Phase I or II study.

But how many clinical investigators do we have in the USA, not just engaged, but truly understanding these technologies and application to the clinic? Unfortunately, even in a very large cancer center, the number of such clinical investigators is limited because of the lack of education opportunities and the limited time to commit to translational research-oriented drug development.

To address these issues, we have established an innovative preclinical research platform: Enhanced Drug-development Guidance and Evaluation (EDGE) Preclinical Solutions. Our mission is to reduce the suffering of breast cancer patients through preclinical operations dedicated to discovering and developing targeted therapies and molecular biomarkers for patient-centered, hypothesis-driven translational/clinical research through extensive collaboration with industry and academia.

EDGE Preclinical Solutions will serve clinicians, basic scientists, and pharmaceutical companies who have a plan to develop promising drugs in breast cancer that can further guide the launch of investigator-initiated clinical trials.

EDGE Preclinical Solutions consists of a dedicated professional multidisciplinary team, including six research faculty members, three clinical faculty members, seven trainees, and six administrative research staff members.

5 Goals

Our unique strength is that we have the capability to align with five goals of the National Center for Advancing Translational Sciences (NCATS):

(1) We have the skills and knowledge needed for translational research;

(2) We are engaging others and forming collaborations;

(3) We are integrating the multiple disciplines, phases of research, and populations addressed;

(4) We are developing robust scientific hypothesis-based proposals that will enable significant advances in translation; and

(5) We are using innovative informatics solutions to advance translational research, with maximal speed that overcomes the hurdles originating from the traditional slow academic approach.

We provide one-stop service, using in-house high-quality in vitro and in vivo experimental resources. Because we have a comprehensive understanding of all the tools and core facilities available inside MD Anderson, we can coordinate all experimental planning for the investigators who come to us.

Ifinvestigators need help in planning and contracting with Pharma, the EDGE faculty and staff can assist. If a company desires a full strategic alliance working with clinical investigators and preclinical development, EDGE Preclinical Solutions can be the matchmaker and can execute the research plan.

The hypothesis-driven preclinical data produced by these activities will be quickly translated into a clinic that is run by world-expert breast cancer clinical investigators. The advantage of this system for clinical investigators is that they can develop preclinical data that will support their clinical strategy, without needing their own bench space or extensive experience in conducting bench research. The advantage for basic researchers is that they do not have to put effort into preclinical data-generation projects that are commonly considered unsuitable for postdoctoral fellows and graduate students.

Currently, 12 investigator-initiated preclinical studies supported by various pharmaceutical companies are being managed by EDGE Preclinical Solutions. Two early-phase clinical trials (NCT01434303 and NCT00921336) based on our preclinical studies have launched, with more to come.

Two Stages

During the development of the EDGE Preclinical Solutions platform, our team learned that translational research in drug development can be divided into two stages:

·The first stage is to facilitate early translation by bringing new compounds or biomarkers to lead to the initial phase drug. This is a critical step for translation of any new cancer drugs, which is well recognized by cancer centers and Pharma.

·The second stage is to select the best translatable molecules or compounds that can benefit the patients by meeting certain milestones asstability, safety, and efficacy, and further develop pre-clinically. This is the area that remains underdeveloped by many cancer centers or that Pharma may not have full access to, and this is where EDGE Preclinical Solutions can contribute significantly to early drug development.

In Summary

In summary, EDGE Preclinical Solutions will provide rapid translation of clinical and preclinical findings via a comprehensive preclinical research platform. In contrast to the conventional academic approach to drug development, which may focus on more mechanistic work that will lead to high-impact publications, our strategy of creating a dedicated preclinical platform will help speed up drug development, skipping the possibly redundant experiment just to perfect publication that requires sometimes years of basic work that may still lack a translatable path to efficacious therapy.

We are confident that this change will result in the rapid development of novel drugs that will benefit both industry and academia by arming us with more innovative therapies. But most importantly, this rapid translational approach to developing novel drugs will benefit patients who are in desperate need of better treatment options.

////////////////////////////////////////////

Jangsoon Lee, PhD, is Clinical Research Scientist in the Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Enhanced Drug Development Guidance and Evaluation Preclinical Solutions, at The University of Texas MD Anderson Cancer Center.

Bora Lim, MD, is Assistant Professor of Medicine in the Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Enhanced Drug Development Guidance and Evaluation Preclinical Solutions, at The University of Texas MD Anderson Cancer Center.

With this transformation comes a myriad of new quality measures for cancer programs to capture and report. The ability to do this in a scalable fashion will rely on the right technology solutions.

Thanks to the HITECH Act, nearly all oncology practices today use EHRs of one sort or another. But HITECH failed to mandate that EHRs interoperate with other technology solutions. About a dozen dominant EHR products exist today and many of these systems don’t talk to each other well (or at all). For patients, transferring records between adjacent healthcare facilities still requires getting hundreds of pages printed, transported, and then scanned, even when both facilities are using the same electronic health record system. For providers, suboptimal software from their EHR vendor is often the only option, meaning no freedom to choose best of breed technology.Even when providers spend time duplicating entries into separate systems, they often can not readily access this information when they need it because it has been blocked from flowing back into their EHR.

To realize the healthcare transformation to value that will lead to better outcomes, less hospitalizations, and greater patient satisfaction at economically sustainable costs, physician practices and hospitals need more than just the digitization of their clinic workflow. They need visibility into nationwide population health management benchmarks and tools for better patient engagement; they need technologies that can interoperate. Unfortunately, top EHR vendors have thwarted interoperability and government regulations have not required it to date.

But this month, the critical need for interoperable Health IT reached the national limelight from multiple channels. CMS introduced final stage 3 meaningful use rules, which lay out penalties for non-interoperable Health IT beginning January 1, 2018. The senate introduced a new bipartisan bill designed to strengthen accountability for technology vendors around Health IT interoperability. The Office of the National Coordinator for Health Information Technology (ONC) shared their 10-year interoperability roadmap, which lays out how we can move towards interoperability by the end of 2017. And in a rare twist, the leaders of dominant EHR vendor companies announced a collective commitment to “go arm in arm to work closely with Washington to help alleviate the interoperability-measurement burden faced by the government.”

While this is all good news, the reality is that a well-defined measurement of interoperability will not move the needle if EHR vendors aren’t willing to share information. As described in the Report to Congress on Health Information Blocking from earlier this year, economic and market conditions have resulted in business incentives for some entities to exercise control over electronic health information in ways that unreasonably limit its availability and use. And as ASCO recently announced, reports of information blocking are increasing.

As a patient care and engagement solution for cancer programs that readily integrates with any other EHR vendor, we at Navigating Cancer have experienced interoperability blocking firsthand. Even after healthcare providers have chosen to sign contracts with us, EHR vendors have either announced that they have no plans to interoperate with our application or stalled in making any real progress toward interoperability.

Responding to the government’s announcements around interoperability, Robert Wergin, M.D., the board chair of the American Academy of Family Physicians, said: “Our members and the AAFP are very concerned with the very slow progress toward achieving truly interoperable systems. Furthermore, we strongly believe there is need for increased accountability on industry and decreased accountability on those who are using their inadequate products. We need more than a roadmap; we need action.”

Will health IT interoperability happen in stride with our transformation to value-based payment models, or will that become the bottleneck?

In 2011, no Medicare payments were made through alternative payment models; by 2014, approximately 20% of payments were made this way.In January of this year, Health and Human Services (HHS) Secretary Sylvia M. Burwell set goals for 30% of traditional Medicare payments to be tied to value-based payment models by the end of 2016, and 50% to be tied to such models by the end of 2018. HHS also set the explicit goal of tying 85% of all traditional Medicare payments to quality or value by 2016 and 90% by 2018. And implementation of the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), signed into law in April of this year, poses a major opportunity to transform healthcare delivery to value through the new Merit-Based Incentive Payment System (MIPS). Within the next few years, multitudes of practices across the nation will embark on the transition to value.

With interoperable EHRs, we will not only save patients and providers the time and energy required to print and scan documents and input duplicate entries; we will finally be able to use the wealth of data that is now amassing to learn about medical practice at the national scale, improve outcomes across the board, realize risk-stratified care delivery and meet the requirements of the alternative payment models that are taking hold. Health IT needs mandatory and explicit standardization for the mechanism by which software programs can talk to one another, called application program interfaces (APIs). We encourage all stakeholders to add your voice to the call for explicit interoperability requirements now.

“In my heart there was a fighting that would not let me sleep…Our indiscretion sometime serves us well, when our deep plots do pall; and that should learn us there’s divinity that shapes our ends…”

Such are the pains that grow and grow and keep us from living a comforting life. The tumult that shudders and causes pain relives in our dreams. We march to the cry of the pained and the harmed to sooth and comfort as our comfort is discomforted, yet we march on in search of love for humanity. The wakeful moments when sleep surrounds and the flesh is laid bare, the white sinews glisten as the red blood congeals under the surgeon’s scalpel. Time is spent to heal.

“Tis dangerous when the baser nature comes between the pass and fell incensed points of mighty opposites.”

The argument ensues between the physician adamant and rigid in his demand to serve his fellowman comes face to face with the mandates of the powerful and finds himself at odds to do right or acquiesce to the tyranny. And yet when all the power is drained from the powerful the end is the same between the two:“A man may fish with the worm that hath eat of a king, and eat of the fish that hath fed of that worm.”What lies at the end is the monument, a testament to the grave-maker;“the houses he makes last till doomsday.”The power like time is fleeting. The madness is also passing. The arrow of time flies and having flown it brings a strange opacity to the past and color to the future. Some are bewildered by the strangeness of that hue, easily moved and rendered unmoving to all other voices save their own. Reason is imprisoned by their desires. All is material. All is passion.

“Give me that man that is not passion’s slave and I will wear him in my heart’s core, ay, in my heart of heart…”

Through reason and deductive efforts the doctor must understand the nuance of a wince, a growth, a loss of desire, of melting flesh, of fragile bones and via that knowledge plead with the consolation of his virtuous thoughts to end what nature or nurture has begun. In doing so, end the“thousand natural shocks that flesh is heir to…”and render health or find the blanket of comfort and soothe to console the imperiled life. A doctor is indeed the very firmament of reason. His virtue is in to mend, to heal, to seek and to reason.

“The spirit that I have seen, may be a devil and the devil hath power t’assume a pleasing shape…”

When with suddenness and without warning there follow uncalled for unexpected riches in the name of ‘good for the many,’ the spark of question must also follow. Is the individual not the portion of the whole community or society and does not making him or her, the sole purpose of all endeavors? Healing him may yet heal the whole! Yet in these heady times the good of the many betrays the good of the one. He or she is lead to the gallows forsaken under the premise of ex-multis. The powerful then“abuses me to damn me.”Ruthless desires overtake to circumvent the need of the one under the egalitarian umbrella. After all such actions are the consequence of thought that churns and bleeds the fiscal brain with the comfort of;“What is a man if his chief good and market of this time be but to feed and sleep.”And think,“That capability and godlike reason to fust in us unus’d,”is but bestial oblivion.

“What a piece of work is a man, how noble in reason, how infinite in faculties, in form and moving how express and admirable, in action how like an angel, in apprehension how like a god! the beauty of the world, the paragon of animals—and yet, to me, what is this quintessence of dust?”

The physician devotes his life in the learning, finding new ways to limit agony, new methods to purge disquiet and new techniques to ward off discomfort. He marches to the beat of the infirmed and the vulnerable. Power and riches do not entice him or her; the need drives him. To quell, to soothe and“to take arms against a sea of troubles and by opposing end them,”is the quintessence of his being. The wretchedness of the body’s decay, do not fend him or her off. She whispers softly and labors with,“grunts and sweats under the weary life”each day and night to bring solace to her fellow being. The doctor in her cries as she looks upon her patient,“What is he whose grief bears such an emphasis, whose phrase of sorrow conjures the wand’ring stars and make them stand like wonder-wounded hearers?”This then is also her salvation. The quiet and hum of life, healed! For most physicians feel as Hamlet feels; “O God, I could be bounded in a nutshell and count myself a king of infinite space, were it not that I have bad dreams."And those dreams are the voices of sorrow, of pain, of anguish and anxiety.

“We defy augury. There’s a special providence in the fall of a sparrow. If it be now, ’tis not to come. If it be not to come, it will be now. If it be not now, yet it will come—the readiness is all. ”

We act as if our actions have little or no negative consequences. The unintended ones lurk underneath and yet we defy the omens, the dull grey beads of disaster that come in slow but hypnotizing fashion clouding the brain.“I shall win at the odds,”is the only thought and doggedly marches to that drumbeat. Nietzsche observed,“ Not reflection, no – true knowledge, an insight into the horrible truth, outweighs any motive for action…”We do arrive at incremental truths about the state of the state in medicine and yet with a flourish of this and that we do away with the warning signs and blink them into obscurity. Their minds are made up. It is what they must do and there the illogic fails for the powerful. For in the end,“And thus the native hue of resolution is sicklied o'er with the pale cast of thought, and enterprises of great pith and moment with this regard their currents turn awry and lose the name of action.”

Polonius advice to his son, Laertes:“This above all: to thine own self be true, And it must follow, as the night the day, Thou canst not then be false to any man,”is remarkable in its hypocrisy. Whereas he is the meddling intellectual that proffers from the inferences he draws to influence the mighty king, he simultaneously offers that Hamlet, without proper reasoning, is mad,“Though this be madness, there is method in’t.”

There are many who embody the flesh of Polonius. They contrive and conjure to manipulate circumstance. These clever and studied orphans of untruth live in the dichotomy of their stardom and villainy; one desired the other earned! They spin from the wombs of their mentality a web so intricate that it confounds the minds of many. The complexity so intricately weaved that only simplicity alone can undo. Yet the wandering, believing minds that cannot chart the course to reason find ways and means to consolidate their thinking and in so doing any words to the contrary that attempt to alienate such unholy wisdom are demonized. The vile mechanism meanwhile feeds the;“Eyes without feeling, feeling without sight, ears without hands or eyes, smelling sans all…”There are also many a Rosencrantz and Guildenstern in society willing to take on the task of distraction, of execution of opinions and reviling sense with nonsense to gain favor and trust of the kings. These are fools that“cleave the general ear with horrid speech, make mad the guilty and appal the free, confound the ignorant and amaze indeed the very faculties of eyes and ears.”These are charlatans, whose folly is only known to those that reason and think and who understand and wait with patience and true knowledge. For villainy“though it have no tongue, will speak with most miraculous organ.”Eventually!

In truth, several powerful forces are at work to drive private practices and hospitals into closer working relationships. These include financial pressures on private oncologists due to lower Medicare reimbursements under the Medicare Modernization Act of 2003, the move towards integrated delivery systems and accountable care organizations. There is no credible data showing 340B hospitals are buying up oncology practices any faster than hospitals outside the program.

The 340B program was specifically designed to give safety-net hospitals an additional funding mechanism to stretch their resources. Since they must serve high percentages of poor patients in order to be eligible for the program, savings from 340B are de facto used to help the underserved.

Private oncologists regularly shunt their poorest patients to the nearest safety-net provider for treatment. Why? Because they make little or no money on these individuals. In turn, safety-net hospitals are obligated to treat all patients, regardless of their ability to pay. This is why they receive discounted chemo drugs from the pharmaceutical industry under 340B. I could understand private oncologists’ resentment more if they actually treated the underserved. Most do not.

Safety-net hospitals sometimes do charge more for oncology services to our insured patients – because we must shoulder the enormous burden of caring for all the people who cannot pay for treatment. Hospitals also offer a much broader range of oncology services, including advanced diagnostics, surgery, radiation therapy, infusion services, patient and family counseling, home care services and palliative care.

The 340B program grew between 2005 and 2011 for two reasons. First, Congress made rural hospitals eligible – most of which have 25 beds or less. Second, the Health Resources and Services Administration changed its bookkeeping rules, requiring hospitals to register off-site clinics as separate 340B entities. In fact, since 2010 there have been only six net-new Disproportionate Share Hospital added to the program.

As much as they would like, private oncologists cannot turn the clock back to better financial times. Changes in the healthcare marketplace are steadily pushing specialty practices of all kinds into the arms of hospitals. Blaming the 340B drug discount program is both misleading and unproductive.

There are currently more than 3.2 million breast cancer survivors in the United States. During Breast Cancer Awareness Month, related news in the media typically includes patient stories, celebrations, and treatment options. Not as well covered in the lay media, though, is another aspect of the disease that affects survivors – i.e., the risk of developing lymphedema.

This life-altering abnormal accumulation of fluid just underneath the skin is one of the most common side effects following treatment for breast cancer and can affect a person’s ability to complete daily tasks, as well as self-image. If left untreated, breast cancer-related lymphedema will continue to progress, causing more serious side effects over time. Research has found that the best treatment for lymphedema is to minimize the risk of developing it.

“Strength After Breast Cancer” is an evidence-based rehabilitation program designed to minimize a woman’s risk of developing lymphedema. The program begins with educating survivors about all aspects of lymphedema and giving participants an individualized assessment of strength, range of motion, and upper body issues. Physical therapists then work with patients in small-group settings to teach techniques that will restore strength and encourage a healthy exercise regimen that will last a lifetime. Slowly progressive strength training has been shown to reduce the risk of developing lymphedema and can reduce the risk of lymphedema symptoms worsening.

The program is a joint creation of Kathryn H. Schmitz, PhD, MPH, Senior Fellow in the Center for Clinical Epidemiology and Biostatistics at Abramson Cancer Center of the University of Pennsylvania, and therapists from Good Shepherd Penn Partners, a Philadelphia-based post-acute therapy provider. A grant awarded to Dr. Schmitz from the National Cancer Institute funded the effort to translate the results of a large clinical trial into a program that could be broadly disseminated to breast cancer survivors across the U.S. and beyond.

The program is based on the results of the randomized, controlled Physical Activity and Lymphedema (PAL) trial, which assessed the safety of progressive strength training in breast cancer survivors, who participated in a supervised, slowly progressive strength training program. Results published in The Journal of the American Medical Association (2010:304:2699-2705) and the New England Journal of Medicine (2009;361:664-674) showed that supervised, slowly progressive strength training is safe for breast cancer survivors. Additionally, women who performed strength training were less likely to develop lymphedema than those who were not strength training.

In the past five years, Strength after Breast Cancer has grown into one of the largest exercise programs for breast cancer survivors in the country and is recognized by the American Physical Therapy Association as an innovative practice model. At this five-year milestone, a new examination of the PAL trial data and the program will soon be published in the Journal of the National Cancer Institute. Giving light to the common challenge of translating research findings into real-world tactics, the new data highlight that participants in Strength After Breast Cancer received the same benefits as participants in the original PAL trial.

Prior to the PAL trial, misconceptions existed around exercise in breast cancer survivors. Standard of care included discouraging survivors from lifting objects greater than about five pounds, which left many survivors unable to perform simple daily tasks, such as handling groceries or even holding children. Despite the clinical evidence, many health care providers still discourage this activity, instilling unnecessary fear and limitations on survivors; yet, if done properly, exercise can be extremely beneficial.

Specialists in the Strength After Breast Cancerprogram work to ensure that participants learn correct form when strength training and stress common errors that may lead to injury. Participants are encouraged to “start low and progress slow,” as the program is shown to work best when therapists collaborate with patients to build a regimen based on their individual needs and health goals.

Lymphedema is a life-long condition. One way to minimize the risk of developing lymphedema is a simple exercise routine. Moving forward, I challenge all those working with cancer patients to encourage those at risk, or already diagnosed, to adopt an appropriate, supervised exercise regimen and to meet with a physical therapist early -- ideally, at the time of diagnosis. When any degree of physical therapy is included in the overall treatment package, patients are more likely to experience a pleasant and safe recovery.

I have had the pleasure of working closely with survivors and their caregivers since the inception of the program atGood Shepherd Penn Partners in 2011. Day after day, participants continually express their gratitude for providing them with the tools to take back their strength. Empowering cancer survivors’ to improve their health is crucial for complete restoration.

Andrea Branas is Lead Physical Therapist for Good Shepherd Penn Partners at the Abramson Cancer Center of the University of Pennsylvania. She received her MSE from the University of Pennsylvania and her MPT from the University of the Sciences in Philadelphia. Good Shepherd Penn Partners is home to one of the largest teams of Certified Lymphedema Therapists in the nation. In addition to Strength After Breast Cancer, Good Shepherd Penn Partners offers a complete rehabilitation plan for lymphedema including all aspects of CDT, Complete Decongestive Therapy; as well as physical therapy-based treatment for cancer related fatigue. Strength After Breast Cancer is also available via UCSF Medical Center and Virtua Health. For more information, visit www.pennpartners.org/strength